The present invention relates to a fast-acting formulation of human recombinant insulin.
Since the production of insulin by genetic engineering, at the start of the 1980s, diabetic patients have benefited from human insulin for their treatment. This product has greatly improved this therapy since the immunological risks associated with the use of non-human insulin, in particular porcine insulin, are eliminated.
One of the problems to be solved for improving the health of diabetic patients is to provide them with insulin formulations that provide a hypoglycemic response similar in terms of kinetics to the physiological response generated by the start of a meal, to enable them to not anticipate the start of their meal time and to perform an insulin injection at the start of the meal.
It is nowadays accepted that the provision of such formulations is essential for the best possible management of the disease.
Genetic engineering has provided a response with the development of rapid insulin analogs. These insulins are modified on one or two amino acids so as to be more rapidly distributed in the blood compartment after subcutaneous injection. These insulins Lispro (Lilly), Novolog (Novo) and Apidra (Aventis) are stable insulin solutions with a hypoglycemic response similar in terms of kinetics to the physiological response generated by the start of a meal. Consequently, patients treated with these rapid insulin analogs no longer have to anticipate their meal time, but can perform the insulin injection at the start of the meal.
The principle of rapid insulin analogs is to form hexamers at a concentration of 100 IU/mL to ensure the stability of the insulin in the commercial product, while at the same time promoting very fast dissociation of these hexamers into monomers after injection so as to obtain a rapid action.
Human insulin as formulated in its commercial form does not make it possible to obtain a hypoglycemic response that is close in terms of kinetics to the physiological response generated by the start of a meal, since, at the concentration of use (100 IU/mL), in the presence of zinc and other excipients such as phenol or cresol, it assembles in the form of a hexamer, whereas it is active in monomer and dimer form. Human insulin is prepared in the form of hexamers to be stable for up to 2 years at 4° C., since, in the form of monomers, it has a very high propensity to aggregate and then to fibrillate, which makes it lose its activity. Furthermore, in this aggregated form, it presents an immunological risk to the patient.
Dissociation of the hexamers into dimers and of the dimers into monomers delays its action by nearly 20 minutes when compared with a rapid insulin analog (Brange J., et al., Advanced Drug Delivery Review, 35, 1999, 307-335).
The drawback of rapid insulin analogs is the modification of the primary structure of human insulin. This modification leads to variations of interaction with the insulin receptors present on a very large number of cell lines, since it is known that the role of the insulin in the body is not limited to its hypoglycemiant activity. Although numerous studies have been performed in this field, it cannot be determined at the present time whether these insulin analogs all have the physiological properties of human insulin.
Furthermore, the kinetics of passage of insulin analogs into the blood, and their kinetics of glycemia reduction, are not optimal and there is a real need for a formulation that has an even shorter action time so as to approach the kinetics of healthy patients.
The company Biodel proposed a solution to this problem, with a human insulin formulation comprising EDTA and citric acid, as described in patent application US 2008/39365. EDTA, via its capacity to complex zinc atoms, and citric acid, via its interactions with the cationic parts, are described as destabilizing the hexameric form of insulin and thus reducing its action time.
However, such a formulation has several drawbacks.
Firstly, the injection of a solution containing citric acid may cause pain at the site of injection, which was indeed reported during various clinical studies performed by Biodel, Business Wire (Sep. 8, 2008).
Moreover, the use of a chelating agent such as EDTA, which is not specific for the zinc atom, may lead to side effects.
Since the use of fast-acting insulin is performed three times a day for type I and type II diabetics, the pain associated with the administration of the product is unacceptable to the patients, and the risks of possible side effects due to the excipients must be avoided at all costs.